tbuckley/cabot-search huggingface dataset:
EXTH-26. MICROGLIA-SPECIFIC DISRUPTION OF SIALIC ACID-SIGLEC-9/E INTERACTIONS: A NOVEL IMMUNOTHERAPY AGAINST GLIOBLASTOMA?
Authors: Philip Schmassmann, Julien Roux, Nazanin Tatari, Tomas A Martins, Marie-Françoise Ritz, Tala Shekarian, Heinz Laeubli, Gregor Hutter
Journal: Neuro-Oncology (2022)

Abstract Recently, ‘don’t eat me’-signals like CD47 have emerged as novel innate immune checkpoints, enabling cancer cells to evade clearance by phagocytes such as microglia (MG) or monocyte-derived cells (MdCs). Here, we aim at defining the role of inhibitory Siglec-9 in human and its mouse homologue Siglec-E in innate-centered immunotherapy against GBM. TCGA RNA-sequencing data revealed a significant correlation between high expression of immunoinhibitory SIGLEC9 and poor survival in GBM patients (log-rank p = 0.02). Using a CT-2A orthotopic GBM mouse model with MG-specific spatio-temporal deletion of Siglece (Sall1CreERT2 x Sigleceflox) , we observed high MG-proliferation upon Siglece knockout (Ki-67+ MG 14.8% in Crenegvs. 34.9% in Creposp &amp;lt; 0.0001) accompanied by an enhanced microglial GBM-cell uptake (5.6% in Crenegvs. 12.3% in Crepos, p &amp;lt; 0.001). By extending the Siglece knockout to the MdC compartment (Cx3cr1CreERT2x Sigleceflox) we observed a significantly prolonged survival in the Crepospopulation (21d in Crenegvs. 27d post-tumor injection in Crepos, p = 0.018), which could be further promoted by combining Siglece knockout with CD47 blockade (11% long-term remission in Crepos+ anti-CD47). Proteomics analysis revealed increased antigen processing and presentation capabilities of SigleceKOMdCs which was confirmed by ex-vivo OT-1 cross-presentation assays. This increased T cell priming upon MdC SigleceKOwas further boosted by addition of anti-PD1 antibody to the SigleceKO+ anti-CD47 combination. Resulting in 23% of animals experiencing long-term remission in the triple treatment arm, even after tumor re-challenge. Genetic targeting of sialic acids, the ligand for Siglec receptors, on CT-2A cells (GNE-KO), resulted in increased GBM-cell phagocytosis by MG and MdCs and less exhausted tumor-infiltrating CD8+ T cells (14.8% in WT vs. 5.9% in GNE-KO, p = 0.003). In a translational approach, we are currently testing anti-Siglec-9 treatment regimens in patient GBM explants, cultured for 5 days in perfusion bioreactors.
RBIO-04. STEREOTACTIC RADIOSURGERY REPROGRAMS MACROPHAGE, MICROGLIA, AND CD8+ T CELL POPULATIONS IN THE GLIOBLASTOMA IMMUNE MICROENVIRONMENT
Authors: Jacob S Young, Nam Woo Cho, Calixto-Hope Lucas, Kyounghee Seo, Raquel Santos, Joanna J Phillips, Tomoko Ozawa, Mitchel S Berger, David Raleigh
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Fractionated radiotherapy is a first-line treatment for glioblastoma, but daily ionizing radiation prevents durable immune infiltration of the tumor microenvironment. Hypofractionated radiotherapy is used to treat glioblastomas at recurrence, but the impact of hypofractionated radiotherapy on the glioblastoma immune microenvironment is incompletely understood. Here we define immune microenvironment changes across multiple immunocompetent intracranial mouse models of glioblastoma after treatment with ionizing radiation mimicking stereotactic radiosurgery (SRS) in humans. METHODS Syngeneic GL261 (3x105 cells/mouse) or SB28 glioblastoma cells (3x104 cells/mouse) were implanted into the frontal lobe of immunocompetent C57BL/6J mice (18 mice/arm x 4 arms). Intracranial bioluminescence was used to assess glioblastoma growth. After tumor engraftment, glioblastomas were treated with conformal SRS (18Gy/1Fx) or sham. Glioblastomas were collected for histologic, single-cell, or molecular analyses 5 days after treatment (6 mice/arm) or at the time of euthanasia after monitoring for survival (12 mice/arm). Glioblastoma immune microenvironment responses were assessed using (1) H&amp;E, (2) single cell mass cytometry (CyTOF) or IHC to define or validate immune cell changes, respectively, or (3) multiplexed cytokine assays to elucidate molecular mechanisms reprograming the glioblastoma immune microenvironment in response to SRS. RESULTS SRS attenuated glioblastoma growth and prolonged survival compared to sham treatment in both immunocompetent intracranial mouse models (GL261: 14 days versus 27 days, p&amp;lt; 0.001, SB28: 19 days versus 22 days, p=0.001). CyTOF showed SRS decreased immunosuppressive macrophage infiltration and increased microglia or CD8+ T cell infiltration of the glioblastoma immune microenvironment. Histologic analyses validated T cell and microglia infiltration after SRS. Glioblastoma cytokine analysis revealed inhibition of pro-tumor/anti-inflammatory cytokines (IL6, LIF) after SRS. CONCLUSIONS Single-fraction SRS durably reprograms glioblastoma macrophage, microglia, and CD8+ T cell populations in preclinical models, suggesting SRS or inhibition of pro-tumor/anti-inflammatory mechanisms underlying the immunosuppressive glioblastoma microenvironment represent immunogenic therapies that may offer a benefit to patients with glioblastoma.
CTNI-33. CSNO2012001 STUDY: A PHASE III TRIAL ON ADJUVANT TEMOZOLOMIDE CHEMOTHERAPY WITH OR WITHOUT INTERFERON-ALPHA IN NEWLY DIAGNOSED HIGH-GRADE GLIOMAS
Authors: ZhongPing Chen, Chengcheng Guo, JianGen Chen
Journal: Neuro-Oncology (2022)

Abstract Purpose The therapeutic efficacy and toxicity of the combination of temozolomide (TMZ) with interferon-alpha (IFN-α) and TMZ alone were compared in newly diagnosed high-grade glioma (HGG) patients.Patients and Methods Following surgery, patients with newly diagnosed HGG (World Health Organization [WHO] grade 3 or 4)were eligible and randomized into two groups. All the patients were received standard radiotherapy concurrent with TMZ. After a 4-week break,patients in group A received standard TMZ (200mg/m2 for 5 days) combined with interferon-α (3mIU, subcutaneous, d1, d3, and d5) every 28 days. Patients in group B were received standard TMZ.Results A total of 199 HGG patients were enrolled, with a median follow-up time of 77.9 months. The median overall survival (OS) of patients in the TMZ+IFN group was significantly longer than that in the standard group, although the progression-free survival (PFS) of both groups was similar . In grade 3 gliomas, the median OS was 39.57 months in the TMZ+IFN group versus 29.40 months in TMZ alone. The median PFS was also longer in the TMZ+IFN group (24.33 months) than that in the TMZ group (14.13 months) . In grade 4 gliomas, the difference in PFS survival between TMZ+IFN and TMZ group showed no significant difference . However, the TMZ+IFN group had a longer OS than that of the TMZ alone group. TMZ+IFN also significantly improved the OS in O6-methylguanine-DNA methyltransferase (MGMT) unmethylation patients. The incidence of toxic effects such as neutropenia, thrombocytopenia, anemia, increased transaminase, skin reactions, fatigue, nausea, or vomiting, and skin reactions were similar in both groups. However, seizure and influenza-like symptoms were more common in the combination group but can be easily controllable.Conclusions Compared with the standard regimen, TMZ+IFN combination treatment could prolong the survival time of HGG patients, especially MGMT promoter unmethylated patients, and the toxicity remained tolerable.
EXTH-102. PLASMA AND CEREBROSPINAL FLUID (CSF) PHARMACOKINETICS (PK) OF MIRDAMETINIB IN A NON-HUMAN PRIMATE (NHP) MODEL
Authors: Cynthia Lester McCully, Todd Shearer, Andrea Gross, Abraham Langseth, Cody Peer, Kristin Killoran, Rafael Cruz Garcia, William Figg, Brigitte Widemann
Journal: Neuro-Oncology (2022)

Abstract Mirdametinib is a MEK inhibitor with reported CSF penetration in pre-clinical models. Murine studies reported ERK phosphorylation inhibition in brain tissue at 1.15 nM (0.73 ng/mL) and tumor cell lines at 0.33–0.59 nM (0.16-0.28 ng/mL). A phase II clinical trial evaluating mirdametinib for neurofibromatosis type 1-related plexiform neurofibromas reported a 42% partial response rate and a mean plasma exposure (AUC0-12h) of 443 h*ng/mL. This study determined the plasma and CSF pharmacokinetic (PK) profile of mirdametinib in a non-human primate (NHP) model where CSF penetration serves as a proxy for CNS penetration. METHODS Four NHP received mirdametinib PO q.d, 0.50 mg/kg, in serial studies as a single dose (Single-Dose), three doses (Multiple-Dose), or IV, 0.20 mg/kg, followed by paired plasma and CSF sample collections through 96 hours. Mirdametinib was quantified by LC-MS/MS. PK parameters were calculated via noncompartmental methods. Plasma protein binding was determined by rapid equilibrium dialysis. RESULTS Mean □ standard deviation values reported. Three subjects were evaluable for both plasma (total and unbound) and CSF drug concentrations. Plasma – AUClast: Single-Dose 500.3 □ 253.4 and IV 552.3 □ 43 h*ng/mL; AUCtau: Multiple-Dose 456.3 □ 120.6 h*ng/mL. CSF Cmax (ng/mL): Single-Dose 0.43 □ 0.18, IV 2.0 □ 1.8, Multiple-Dose 0.56 □ 0.18. CSF Penetration (%): Single-Dose 1.3 □ 0.45, IV-1.6 □ 0.95 (AUCcsf-last:AUCplasma-last); Multiple-Dose 1.3 □ 0.56 (AUCcsf-tau:AUCplasma-tau). CSF/unbound plasma ratios ranged from 2.5-3.0 Plasma free fraction (%): 0.52 □ 0.1. CONCLUSION Notable mirdametinib CSF penetration was demonstrated in this NHP model. A higher CSF to unbound plasma ratio suggests that the efflux of mirdametinib from the CSF was delayed. The NHP CSF Cmax approached the ERK phosphorylation inhibition concentrations previously reported. The ability of this NHP model to predict human PK parameters was demonstrated via the comparable NHP to patient plasma exposure reported in the Phase II clinical trial.
CTNI-14. A PHASE 0 ‘TRIGGER’ TRIAL OF NIRAPARIB IN NEWLY-DIAGNOSED GLIOBLASTOMA PATIENTS
Authors: Nader Sanai, Tigran Margaryan, Jennifer Molloy, William Knight, Jocelyn Harmon, Amy Hong, John Wanebo, William Kennedy, Michael Garcia, Igor Barani, Wonsuk Yoo, An-Chi Tien, Artak Tovmasyan, Shwetal Mehta
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients to a therapeutic regimen of niraparib plus fractionated radiotherapy when high unbound drug concentrations are present in gadolinium-nonenhancing tumor. METHODS Presumed newly-diagnosed GBM patients received 4 days of niraparib (300 mg QD) prior to planned resection at 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase and was defined as unbound [niraparib] &amp;gt; 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. PARP inhibition was assessed by quantification of PAR induction after 10 Gy ex vivo irradiation in surgical tissue compared to non-irradiated control tissue. Patients with unmethylated MGMT tumors exceeding the PK threshold were eligible for expansion phase dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib. RESULTS Nineteen patients were enrolled into the Phase 0 study; all tumors met the study’s PK threshold and five unmethylated patients continued onto the expansion phase. One expansion phase patient experienced treatment-related Grade 3 serious adverse event (ALT and AST elevation) and four remain on treatment (median 4.2 months). In nonenhancing regions, the mean unbound concentrations of niraparib were 353.4 nM and 331.9 nM in the 3-5 hr cohort (n= 17) and the 8-12 hr (n = 3) cohort, respectively. The suppression of PAR levels after ex vivo radiation was observed in 69% of the patients (11/16). CONCLUSIONS Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor.
QLTI-18. LIQUID BIOPSY: CLINICALLY INTEGRATED RESEARCH IN THE MODERN PANDEMIC ERA
Authors: Abhinav Nannapaneni, Amanda Wigand, Kelly Tundo, Tobias Walbert, James Snyder
Journal: Neuro-Oncology (2022)

Abstract The COVID-19 pandemic forced a redesign of clinical research to adapt to an ever-changing situation while minimizing patient and provider risks and preserving scientific discovery. During the initial surge of COVID-19, elective healthcare services and non-critical research operations were halted. These changes inspired dispersed health care operations and streamlined clinical research. The first wave of COVID-19 hit Detroit, Michigan, in March 2020, consuming Henry Ford Health (HFH), in COVID-19 emergency care. HFH has a clinically integrated liquid biopsy (LB) program where enrolled patients provide an LB sample via venipuncture within 7 days of each MRI, typically in the clinic at the point-of-care. Prior to COVID-19, 183 neuro-oncology patients were actively providing LB samples in clinic with a mean of 29.9 specimens monthly. Institutional COVID-19 restrictions on non-critical interactions resulted in months were nearly all outpatient encounters utilized telemedicine and decentralized testing off-site from research operations. This halted LB procurement to 4.55 specimens monthly during early pandemic months. To reduce patient-provider exposure, LB specimens were then procured with the venipuncture for MRI which streamlined LB operations and improved the patient experience. After this change, LB specimen procurement returned to near pre-pandemic levels with a mean of 28.1 monthly specimens, despite a significant population utilizing video visits and imaging at satellite or non-HFH centers. The pandemic forced adaptations to patient encounters that have changed how healthcare is delivered, resulting in parallel changes in research that must be considered in the design of future studies.
CTIM-11. SINGLE-CENTER, OFF-LABEL NEOADJUVANT PEMBROLIZUMAB FOR TREATMENT OF RECURRENT GBM AT UCLA
Authors: Shivani Baisiwala, Lu Sun, Benjamin Ellingson, Robert Prins, Phioanh L Nghiemphu, Timothy Cloughesy, Richard G Everson
Journal: Neuro-Oncology (2022)

Abstract Neoadjuvant drug administration provides a window of opportunity for developing novel therapies. Specifically, neoadjuvant pembrolizumab (PD1 checkpoint inhibitor) has the potential for improving understanding of immunomodulatory effects on the tumor microenvironment and for treating recurrent GBM. It is known that a functional immune deficit exists within the tumor T-lymphocyte compartment. As pembrolizumab promotes lymphocyte infiltration, it may contribute to antitumor effects in the neoadjuvant setting. Our previous randomized clinical trial (RCT) suggested that neoadjuvant pembrolizumab improved survival for recurrent GBM patients with 1-2 relapses. Here, we sought to extend our original findings and analyze the role of off-label neoadjuvant pembrolizumab in patients with multiple recurrences. We identified a retrospective 22-patient cohort at UCLA. Every patient had a GBM tissue diagnosis, received standard treatment, and had one to five recurrences. Each received off-label neoadjuvant pembrolizumab and surgical resection within 7-21 days. Progression-free (PFS) and overall survival (OS) for our cohort of neoadjuvant-treated patients were calculated as days from surgical resection and compared to historical control data from the original RCT (n = 15 neoadjuvant, 15 adjuvant). Results show that administration of neoadjuvant pembrolizumab in our cohort significantly increased median PFS compared to our historical adjuvant control (114 vs 75 days, p = 0.03). The OS of our neoadjuvant cohort was 294 days as compared to 192 days in the historical control. Both PFS and OS in our neoadjuvant cohort were not statistically different than the historical neoadjuvant cohort (PFSp = 0.08, OSp = 0.13). Since our cohort was not limited to initial recurrences, this data suggests that patients with more advanced recurrences could also benefit from neo-adjuvant therapy. Ongoing work will evaluate the microenvironmental genetic signature induced by pembrolizumab and assess pre-surgical tumor volume so that adequate comparisons can be made with other trials. We believe this promising finding offers novel therapeutic options for those patients with multiple recurrences.
QOL-04. THE EFFECT OF ART THERAPY ON PATIENT AND CAREGIVER QUALITY OF LIFE IN NEWLY DIAGNOSED HIGH GRADE GLIOMA: A PROSPECTIVE PILOT STUDY
Authors: Jamal Mohamud, Kathryn Nevel, Ashley Hildenbrandt, Maggie Girard, Barbra VanderVossen
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND High grade gliomas (HGGs) are incurable primary brain tumors, with limited survival times. Patients experience a variety of physical, cognitive, psycho-social changes that may negatively impact patient’s quality of life (QOL). Moreover, patient caregivers’ QOL are also often negatively impacted. As such, interventions to improve patient and caregiver QOL are needed. This study aims to evaluate whether art therapy positively impacts QOL among patients with HGG and their caregivers. METHODS This is a planned study with a target of 20 newly diagnosed or early treatment HGG patients and their caregiver matches. Each patient (with the option of one caregiver per patient) will participate in six (6) monthly art therapy sessions with licensed art therapists and structured curriculum. Patient and caregiver QOL will be assessed before, during, and after the six-month study period using validated scales including the HADS, EORTC-QL-C30, and COQL-C. The data will be aggregated following study completion for statistical modeling. DISCUSSION The positive impact of art therapy on QOL has previously been well established in patients with oncologic and neurologic conditions. However, there is a gap in our understanding of the impact of such therapies among patients with primary neuro-oncologic disorders. These patients face uniquely difficult physical, cognitive, and psychosocial challenges as a result of their unique disease process. It would stand to reason that newly diagnosed HGG patients may benefit from early enrolment and participation in these therapies to improve their overall QOL, particularly shortly after diagnosis and during active anti-cancer therapies. CONCLUSION To our knowledge, this is the first study to assess the impact of such intervention in newly diagnosed HGG patients. This pilot study will assess if early intervention with such therapies can lead to significant changes in patients and/or caregiver measurable QOL metrics.
INNV-11. EIGHTEEN YEARS OF EXPERIENCE WITH TREATMENT OF GLIOBLASTOMA USING TUMOR TREATING FIELDS (TTFIELDS) IN NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM) IN A SINGLE CENTER
Authors: Josef Vymazal, Tomáš Novák, Petr Slanina, Tomáš Kazda, Jan Sroubek, Jan Klener, Tomáš Hrbáč, Martin Syrucek, Aaron Rulseh
Journal: Neuro-Oncology (2022)

Abstract Despite considerable progress in the management of many malignant tumors, the prognosis of the most malignant primary brain tumor, GBM, remains unfavorable. TTFields utilize low intensity electric fields with intermediate frequency (100–500 kHz) that act as an antimitotic, selectively inhibiting growth of rapidly dividing tumor cells by disrupting multiple phases of the cell cycle (metaphase, anaphase, and telophase) resulting in cellular apoptosis. TTFields are delivered via arrays of transducers placed on the patients’ scalp. Between 2004 and August 2021, 54 patients (KPS ≥, 20 female), aged 21.85–77.77 years (mean age 47.41 ± 11.92 years; median 47.88 years) were treated with TTFields for ndGBM, and compared to 52 control patients (15 females); aged 27.03–76.67 years (mean age 51.38 ± 12.55 years; median 51.74 years. All patients from both groups underwent gross total or partial resection of GBM. When available, MGMT promoter methylation status was comparable in both groups. The most frequent AE from TTFields therapy was skin irritation at the array site that usually responded to local corticosteroid application. Patients on TTFields therapy demonstrated improvements in PFS and OS relative to controls (hazard ratio: 0.55, p=0.006; and 0.61, p=0.027 respectively). TTFields average time on therapy was 74.8% (median 82%): median PFS of these patients was 18.16 months. Seven patients with TTFields usage ≤ 60% (23–60%, mean 46.3%, median 53%) had a median PFS of 7.95 months (p=0.0356). Control patients with no TTFields exposure had a median PFS of 11.04 months. In conclusion, this is one of the most extensive studies of ndGBM patients treated with TTFields, covering a period of 18 years in a single center. We demonstrate positive effects of TTFields on both PFS and OS in patients with ndGBM.
CSIG-18. ANTI-TUMOR EFFECTS OF VERTEPORFIN AND PHOTODYNAMIC THERAPY IN COMBINATION WITH STANDARD OF CARE ON PATIENT-DERIVED GBM CELL LINES
Authors: Sweta Sudhir, Maria Anastasiadou, Gabrielle Price, Constantinos Hadjipanayis
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median survival of approximately 15 months. GBM tumorigenicity frequently arises from aberrant signaling transduction pathways involving receptor tyrosine kinases (RTKs), such as EGFR and PI3K. Amplification of the Epidermal Growth Factor Receptor (EGFR) gene upregulates Hippo pathway transcription factors YAP1 and TAZ, leading to tumor cell proliferation, radiation resistance, and poor survival. Verteporfin (VP), also known as Visudyne, is an FDA-approved macular degeneration photosensitizer that has photodynamic effects when combined with 489 nm of light. Additionally, VP is a small-molecule inhibitor of the YAP/TAZ/TEAD complex that has been shown to reduce tumor migration and is in phase I clinical trial as a chemotherapeutic for patients with recurrent GBM. We now investigate if VP is an effective photosensitizer for PDT in GBM and if it enhances the effects of TMZ and RT. Compared to VP alone, VP+PDT reduced the IC50 of VP treatment in GBM cells +/- EGFR amplification. Light activation of VP has a significant antitumor effect as observed with cytotoxicity in comparison to vehicle and VP treated cells (p&amp;lt; 0.01). Compared to control, VP, VP+PDT+TMZ, and CRT show significantly less intravasation (p&amp;lt; 0.01). Furthermore, Western blot analysis shows differential expression of YAP, TAZ and TEAD compared to Control and VP after treatment with VP+PDT. Differential YAP signaling is observed via IF staining in EGFR+ GBM cells treat with VP+PDT. Our research supports the use of VP as a photosensitizer in GBM cells. We found downregulation of the hippo pathway and decrease tumorigenicity of GBM cells. Application of VP-PDT treatment in combination with standard of care may be proven beneficial in GBM patients. We plan to further explore these in vitro findings in mice models and investigate other pathways including immune response with NanoString analysis.